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European Journal of Drug Metabolism and Pharmacokinetics

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https://www.readbyqxmd.com/read/29785610/evaluation-of-strategies-for-the-assessment-of-drug-drug-interactions-involving-cytochrome-p450-enzymes
#1
Jelle Reinen, Martijn Smit, Mira Wenker
BACKGROUND AND OBJECTIVES: Drug-drug interactions (DDIs) can occur when one drug alters the metabolism of another drug. Drug metabolism mediated by cytochrome P450 enzymes (CYPs) is responsible for the majority of metabolism of known drugs and inhibition of CYP enzymes is a well-known cause of DDIs. In the current study, the use of various human liver microsomes (HLM)-based methods to determine occurrence of CYP-mediated metabolism-dependent inhibition (MDI) and possible follow-up studies were evaluated...
May 21, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29785609/evaluation-of-focei-and-saem-estimation-methods-in-population-pharmacokinetic-analysis-using-nonmem-%C3%A2-across-rich-medium-and-sparse-sampling-data
#2
Waroonrat Sukarnjanaset, Thitima Wattanavijitkul, Sutep Jarurattanasirikul
BACKGROUND AND OBJECTIVES: First-order conditional estimation with interaction (FOCEI) is one of the most commonly used estimation methods in nonlinear mixed effects modeling, while the stochastic approximation expectation maximization (SAEM) is the newer estimation algorithm. This work aimed to compare the performance of FOCEI and SAEM methods when using NONMEM® with the classical one- and two-compartment models across rich, medium, and sparse data. METHODS: One- and two-compartment models of the previous studies were used to simulate data in three scenarios: rich, medium, and sparse data...
May 21, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29779093/pharmacokinetics-of-the-novel-selective-non-steroidal-mineralocorticoid-receptor-antagonist-finerenone-in-healthy-volunteers-results-from-an-absolute-bioavailability-study-and-drug-drug-interaction-studies-in-vitro-and-in-vivo
#3
Roland Heinig, Michael Gerisch, Anna Engelen, Johannes Nagelschmitz, Stephanie Loewen
BACKGROUND AND OBJECTIVES: Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism. METHODS: The pharmacokinetics, safety and tolerability of finerenone (1...
May 19, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29752643/effect-of-multiple-doses-of-omeprazole-on-the-pharmacokinetics-safety-and-tolerability-of-roxadustat-in-healthy-subjects
#4
Dorien Groenendaal-van de Meent, Martin den Adel, Jan van Dijk, Begona Barroso-Fernandez, Rachid El Galta, Georg Golor, Marloes Schaddelee
BACKGROUND AND OBJECTIVES: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat. METHODS: This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat...
May 11, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29748821/absorption-distribution-metabolism-and-excretion-of-the-novel-helicase-primase-inhibitor-amenamevir-asp2151-in-rodents
#5
Yoshiaki Ohtsu, Yoko Susaki, Kiyoshi Noguchi
BACKGROUND AND OBJECTIVES: The helicase-primase inhibitor amenamevir (ASP2151) is a novel therapeutic agent which has been approved for the treatment of herpes zoster. The present study examined the pharmacokinetic profile of amenamevir in rodents and compared it with data from the literature of past and current established therapies (acyclovir and valaciclovir) to provide additional data to facilitate drug discovery and proper drug use. METHODS: In situ absorption, blood and plasma radioactivity concentrations, tissue distribution, and excretion were determined using liquid scintillation counting...
May 10, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29744741/effect-of-naltrexone-hydrochloride-on-cytochrome-p450-1a2-2c9-2d6-and-3a4-activity-in-human-liver-microsomes
#6
Haitham AlRabiah, Abdul Ahad, Gamal A E Mostafa, Fahad I Al-Jenoobi
BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. METHODS: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride...
May 9, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29725943/in-vitro-monitoring-of-the-mitochondrial-beta-oxidation-flux-of-palmitic-acid-and-investigation-of-its-pharmacological-alteration-by-therapeutics
#7
Renata Murgasova, Ester Tor Carreras, Julien Bourgailh
BACKGROUND AND OBJECTIVE: The present study was designed to validate the functional assay that enables rapid screening of therapeutic candidates for their effect on mitochondrial fatty acid oxidation. METHODS: The two whole-cell systems (tissue homogenates and hepatocytes) have been evaluated to monitor the total beta-oxidation flux of physiologically important 3 H-palmitic acid by measurement of tritiated water enrichment in incubations using UPLC coupled on-line to radioactivity monitoring and mass spectrometry...
May 3, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29721716/effect-of-gambogenic-acid-on-cytochrome-p450-1a2-2b1-and-2e1-and-constitutive-androstane-receptor-in-rats
#8
Jing Sun, Xiaozhu Tang, Qianqian Xu, Tao Ge, Daiyin Peng, Weidong Chen
BACKGROUND AND OBJECTIVES: Gambogenic acid (GNA), which possesses diverse antitumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. Cytochrome P450 (CYP) enzymes play an important role in the metabolism of most xenobiotics; constitutive androstane receptor (CAR), a nuclear receptor that might be activated by xenobiotics and associated with the expression of some CYPs. In this study, we determined the effect of GNA on multiple rat liver CYP isoforms (CYP1A2, 2B1, and 2E1) and CAR as well as the potential of GNA to interact with co-administered drugs...
May 2, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29704095/pharmacokinetic-profiling-of-butylidenephthalide-and-alisol-b-in-danggui-shaoyao-san-in-rats
#9
Hui-Fei Wu, Xiang-Yu Wang, Ji-Feng Deng, Shi-Jian Quan, Qi Wang, Wei-Rong Li
BACKGROUND AND OBJECTIVE: Danggui-Shaoyao-San (DSS), a famous Chinese formula, has been widely used to treat gynecological disorders since ancient times and has recently showed efficacy in treating Alzheimer's disease. Butylidenephthalide (BDPH) and alisol B (ALI) are recognized as the primary active ingredients of DSS. The objectives of the present study were to evaluate the pharmacokinetic comparative study of BDPH and ALI in herbal extracts and their purified forms. METHOD: A sensitive and specific high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) methodology was developed to determine the concentration level of BDPH and ALI in rat plasma...
April 27, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29691732/impact-of-the-cyp3a5-1-allele-on-the-pharmacokinetics-of-tacrolimus-in-japanese-heart-transplant-patients
#10
Takaya Uno, Kyoichi Wada, Sachi Matsuda, Yuka Terada, Akira Oita, Atsushi Kawase, Mitsutaka Takada
BACKGROUND AND OBJECTIVE: Tacrolimus, a major immunosuppressant used after transplantation, is associated with large interindividual variation involving genetic polymorphisms in metabolic processes. A common variant of the cytochrome P450 (CYP) 3A5 gene, CYP3A5*3, affects blood concentrations of tacrolimus. However, tacrolimus pharmacokinetics at the early stage of transplantation have not been adequately studied in heart transplantation. We retrospectively examined the impact of the CYP3A5 genotype on tacrolimus pharmacokinetics at the early stage of heart transplantation...
April 24, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29637493/the-underrated-risks-of-tamoxifen-drug-interactions
#11
Philip D Hansten
Tamoxifen is a prodrug, and most of the therapeutic effect in treating breast cancer stems from its metabolite, endoxifen. Since cytochrome P450 (CYP) 2D6 is the most important enzyme in the production of endoxifen, drugs that inhibit CYP2D6 would be expected to reduce tamoxifen efficacy. In addition to drug-drug interactions (DDI) involving CYP2D6, there is growing evidence that enzyme inducers can substantially alter the disposition of endoxifen, reducing tamoxifen efficacy. Although the clinical evidence on the impact of CYP2D6 inhibitors on tamoxifen efficacy is mixed, there were serious flaws in many of the studies...
April 10, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29619682/a-population-pharmacokinetic-and-pharmacodynamic-analysis-of-rp5063-phase-2-study-data-in-patients-with-schizophrenia-or-schizoaffective-disorder
#12
Marc Cantillon, Robert Ings, Arul Prakash, Laxminarayan Bhat
BACKGROUND AND OBJECTIVE: RP5063 is a novel multimodal dopamine (D)-serotonin (5-HT) stabilizer possessing partial agonist activity for D2/3/4 and 5-HT1A/2A , antagonist activity for 5-HT2B/2C/7, and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships. METHODS: Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates...
April 4, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29616423/pharmacokinetics-of-the-p-gp-inhibitor-tariquidar-in-rats-after-intravenous-oral-and-intraperitoneal-administration
#13
Peter Matzneller, Manuel Kussmann, Sabine Eberl, Alexandra Maier-Salamon, Walter Jäger, Martin Bauer, Oliver Langer, Markus Zeitlinger, Wolfgang Poeppl
BACKGROUND AND OBJECTIVE: P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood-brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use...
April 3, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29589340/influence-of-nutritional-status-on-the-absorption-of-polyphyllin-i-an-anticancer-candidate-from-paris-polyphylla-in-rats
#14
Feng-Ling Yu, Wei-Liang Gong, Fang-Jiang Xu, Jun-Wen Wu, Shailendra Shakya, He Zhu
BACKGROUND AND OBJECTIVES: Protein-calorie malnutrition (PCM) is one of the most suffered complications in cancer patients. Polyphyllin I (PPI), a saponin isolated from rhizome of Paris polyphylla, is a potential candidate in cancer therapy. In this study, the influence of nutritional status on the absorption of PPI in rats was explored after oral administration. METHODS: PCM rats, namely mal-nourished (MN) rats, were induced from well-nourished (WN) rats by caloric restriction protocol...
March 28, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29577177/ocular-pharmacokinetics-of-25-hydroxyvitamin-d3-after-weekly-supplementation-in-rabbits-using-ultra-performance-liquid-chromatography-tandem-mass-spectrometer
#15
Archit Kumar, Mini P Singh, Tripti Rungta, Ajay Patial, Savita Verma Attri, Bikash Medhi, Radha Kanta Ratho
BACKGROUND AND OBJECTIVES: The protective role of vitamin D supplementation has recently been shown to be present in various ocular inflammatory diseases. The oral supplementation of vitamin D may take time to achieve adequate levels in intraocular fluids. Therefore, the present study was performed to understand the ocular pharmacokinetics of 25-hydroxyvitamin D3 (25D3) in aqueous humor after weekly supplementation of 25D3 in rabbits. METHODS: A total of 21 rabbits were fed orally with 25D3 (7...
March 26, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29557529/clinical-pharmacokinetics-and-drug-drug-interactions-of-elbasvir-grazoprevir
#16
Tony K L Kiang
Elbasvir and grazoprevir, in a fixed-dose combination of 50 and 100 mg, respectively, have received approval to be administered orally once daily, with or without ribavirin, for the treatment of chronic hepatitis C virus (HCV) infections. The absorption characteristics of elbasvir and grazoprevir have been adequately summarized, although differences were observed for grazoprevir (e.g., increased exposure at steady state in patients), but not elbasvir, between healthy and HCV-infected subjects. Inconsistencies with respect to absorption were also reported on the effects of food or acid reducers (famotidine or pantoprazole) in the literature...
March 20, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29542019/in-vivo-red-blood-cells-plasma-partition-coefficient-of-treosulfan-and-its-active-monoepoxide-in-rats
#17
Michał Romański, Anna Zacharzewska, Artur Teżyk, Franciszek K Główka
BACKGROUND AND OBJECTIVES: Treosulfan is a prodrug applied in the treatment of ovarian cancer and conditioning prior to stem cell transplantation. So far, the bioanalysis of treosulfan in either whole blood or red blood cells (RBC) has not been carried out. In this work, the RBC/plasma partition coefficient (Ke/p ) of treosulfan and its active monoepoxide was determined for the first time. METHODS: Male and female 10-week-old Wistar rats (n = 6/6) received an intraperitoneal injection of treosulfan at the dose of 500 mg/kg body weight...
March 14, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29520719/determination-of-puquitinib-in-human-plasma-by-hplc-esi-ms-ms-application-to-pharmacokinetic-study
#18
Jing Zhan, Ya Ding, Benyan Zou, Hai Liao, Wenqi Jiang, Su Li
BACKGROUND AND OBJECTIVE: Puquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients. METHODS: The analytes of human plasma were prepared by liquid-liquid extraction using methyl-t-butyl ether (MTBE)...
March 8, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29520718/pharmacokinetics-and-toxicology-of-the-neuroprotective-e-e-e-methanofullerene-60-63-tris-malonic-acid-c-3-in-mice-and-primates
#19
Joshua I Hardt, Joel S Perlmutter, Christopher J Smith, Kevin L Quick, Ling Wei, Subhasish K Chakraborty, Laura L Dugan
BACKGROUND AND OBJECTIVES: Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C 3 ), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys...
March 8, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29500603/effects-of-ketoconazole-and-rifampicin-on-the-pharmacokinetics-of-nintedanib-in-healthy-subjects
#20
Doreen Luedtke, Kristell Marzin, Arvid Jungnik, Ute von Wangenheim, Claudia Dallinger
BACKGROUND: Nintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib. METHODS: In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences...
March 2, 2018: European Journal of Drug Metabolism and Pharmacokinetics
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